Cool-1 functions as an essential regulatory node for EGFreceptor- and Src-mediated cell growth

Abstract

Cool-1 (cloned-out of library 1) has a key role in regulating epidermal growth factor receptor (EGFR) degradation. Here, we show that Cool-1 performs this function by functioning as both an upstream activator and downstream target for Cdc42. EGF-dependent phosphorylation of Cool-1 enables it to act as a nucleotide exchange factor for Cdc42 and to form a complex with the E3 ligase Cbl, thus regulating Cbl-catalysed EGFR degradation. The EGF-dependent phosphorylation is normally transient; however, Cool-1 phosphorylation is sustained in cells expressing v-Src and is essential for cellular transformation, as well as for v-Src-induced tumour formation in mice. These findings demonstrate that the regulated phosphorylation of Cool-1 is necessary to maintain the balance between normal signalling by EGFR and Src versus aberrant growth and transformation.

YES, a Src Family Kinase, Is a Proximal Glucose-specific Activator of Cell Division Cycle Control Protein 42 (Cdc42) in Pancreatic Islet β Cells

“…Based upon the literature, ␤Pix and Cav-1 are both candidates (21,23) and in ␤ cells serve as the requisite GDI and GEF, respectively, for glucose-induced Cdc42 activation and GSIS (19,20). For example, the Tyr-14 SFK phosphorylation site in Cav-1 is required for Cdc42-Cav-1 interactions, and the Cav-1 Y14F mutant is unable to compete with ␤Pix for Cdc42 association in ␤ cells (20).…”

“…In other cell types Cav-1-Cdc42 and ␤Pix-Cdc42 interactions are dependent on the phosphorylation statuses of both the GDI and GEF. Members of the Src family kinases (SFKs) have been implicated in these crucial phosphorylation events (21)(22)(23)(24)(25). Furthermore, SFKs have been shown to play a role in Cdc42 activation as well as stimulus-induced filamentous actin reorganization in other non-␤-cell types (26,27).…”

A βPix–Pak2a signaling pathway regulates cerebral vascular stability in zebrafish

“…␤Pix can also act independently of Pak by binding Cbl (21). Pix and Pak participate in multiple cellular pathways and are downstream of the EGFR, integrins, and G coupled protein receptors (19,21,22). The in vivo roles of ␤Pix and Pak2 are unknown, but related Pix and Pak genes are critical for neural development in mice and humans (23)(24)(25).…”

“…Although ␤Pix is a guanine exchange factor, it also acts in a GTPase-independent mode to activate Pak through binding of GIT1, followed by localization to focal adhesions (20). ␤Pix can also act independently of Pak by binding Cbl (21). Pix and Pak participate in multiple cellular pathways and are downstream of the EGFR, integrins, and G coupled protein receptors (19,21,22).…”

Scrib, un gène suppresseur de tumeurs impliqué dans la polarité cellulaire

“…Leur activation peut être induite par des facteurs d'échange (GEF) qui catalysent l'échange du GDP par du GTP. βPIX a été initialement décrite comme potentiel facteur d'échange à la fois pour Rac et Cdc42, et son activité est régulée par phosphorylation et semble être plus spécifiquement dirigée vers Cdc42 [28]. Nous avons pu mettre en évidence, grâce à l'utilisation de mutants catalytiquement inactifs, que l'activité GEF de βPIX était absolument nécessaire à sa fonction dans le contrôle de la polarité des astrocytes en migration [14].…”